Abstract
Background: The leptin receptor (LEPR) is an important regulator of leptin activity and resistance. Several single nucleotide polymorphisms (SNP) of LEPR have been linked to diseases accompanying obesity and/or obesity-related diseases in different populations. However, the results from published studies remain inconsistent rather than conclusive. Aim: To investigate whether LEPR SNP are associated with essential hypertension and related metabolic traits in Chinese subjects. Materials and methods: A total of 544 Chinese patients with hypertension and 357 non-hypertensive subjects were screened. The genotypes of LEPR polymorphisms were determined by PCR-restriction fragment length polymorphism methods. Demographic and biochemical characteristics including waist circumference, waist-to-hip ratio, body mass index (BMI), lipids profiles, glucose metabolism, and leptin levels were obtained for analysis. Results: This case-control study showed associations between the frequencies of AA genotype and A allele of Gln223Arg and hypertension (p=0.029, p=0.002, respectively). Furthermore, the Gln223Arg polymorphism was significantly associated with plasma leptin levels (p<0.001), while no correlations between Lys109Arg SNP and hypertension were found. Multivariate logistic regression analysis evidenced that A allele carriers of Gln223Arg (AA+AG) showed higher risks of hypertension than GG carriers after adjustment of age and sex (adjusted odds ratio: 1.549, 95% confidence interval: 1.031-2.036, p=0.035). BMI, fasting serum insulin, oral glucose tolernace test (OGTT)-2h glucose, serum leptin, as well as LDL-cholesterol (LDL-C) levels were also independent risk factors of hypertension in this population. In addition, significant associations were observed between the Gln223Arg and Lys109Ar g SNP and serum total cholesterol, LDL-C, and fasting plasma glucose levels in hypertensive patients. Besides, A allele of Gln223Arg had raised diastolic blood pressure, compared with GG carriers (p=0.001). While variance of Lys109Arg was associated with waist-to-hip ratio, OGTT-2h glucose, and homeostasis model assessment of insulin resistance (p<0.05). Conclusions: LEPR polymorphisms may be a marker for susceptibility to essential hypertension in Chinese subjects, and be involved in the development of several features including dyslipidemia and impaired glucose regulation in hypertension subjects.
Similar content being viewed by others
References
Shi G, Gu CC, Kraja AT, et al. Genetic effect on blood pressure is modulated by age: the Hypertension Genetic Epidemiology Network Study. Hypertension 2009, 53: 35–41.
Agarwal A, Williams GH, Fisher ND. Genetics of human hypertension. Trends Endocrinol Metab 2005, 16: 127–33.
Kohara K, Tabara Y, Nakura J, et al. Identification of hypertension-susceptibility genes and pathways by a systemic multiple candidate gene approach: the millennium genome project for hypertension. Hypertens Res 2008, 31: 203–12.
Woods AJ, Stock MJ. Leptin activation in hypothalamus. Nature 1996, 381: 745.
Takizawa H, Ura N, Saitoh S, et al. Gender difference in the relationships among hyperleptinemia, hyperinsulinemia, and hypertension. Clin Exp Hypertens 2001, 23: 357–68.
Galletti F, D’Elia L, Barba G, et al. High-circulating leptin levels are associated with greater risk of hypertension in men independently of body mass and insulin resistance: results of an eight-year follow-up study. J Clin Endocrinol Metab 2008, 93: 3922–6.
Dunbar JC, Hu Y, Lu H. Intracerebroventricular leptin increases lumbar and renal sympathetic nerve activity and blood pressure in normal rats. Diabetes 1997, 46: 2040–3.
Portoles O, Sorli JV, Frances F, et al. Effect of genetic variation in the leptin gene promoter and the leptin receptor gene on obesity risk in a population-based case-control study in Spain. Eur J Epidemiol 2006, 21: 605–12.
Quinton ND, Lee AJ, Ross RJ, Eastell R, Blakemore AI. A single nucleotide polymorphism (SNP) in the leptin receptor is associated with BMI, fat mass and leptin levels in postmenopausal Caucasian women. Hum Genet 2001, 108: 233–6.
Nannipieri M, Posadas R, Bonotti A, et al. Polymorphism of the 3′-untranslated region of the leptin receptor gene, but not the adiponectin SNP45 polymorphism, predicts type 2 diabetes: a population-based study. Diabetes Care 2006, 29: 2509–11.
Saukko M, Kesaniemi YA, Ukkola O. Leptin receptor Lys109Arg and Gln223Arg polymorphisms are associated with early atherosclerosis. Metab Syndr Relat Disord 8: 425–30.
Constantin A, Costache G, Sima AV, Glavce CS, Vladica M, Popov DL. Leptin G-2548A and leptin receptor Q223R gene polymorphisms are not associated with obesity in Romanian subjects. Biochem Biophys Res Commun 2010, 391: 282–6.
Rosmond R, Chagnon YC, Holm G, et al. Hypertension in obesity and the leptin receptor gene locus. J Clin Endocrinol Metab 2000, 85: 3126–31.
Masuo K, Straznicky NE, Lambert GW, et al. Leptin-receptor polymorphisms relate to obesity through blunted leptin-mediated sympathetic nerve activation in a Caucasian male population. Hypertens Res 2008, 31: 1093–100.
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985, 28: 412–9.
Haynes WG, Morgan DA, Walsh SA, Mark AL, Sivitz WI. Receptor-mediated regional sympathetic nerve activation by leptin. J Clin Invest 1997, 100: 270–8.
Harlan SM, Morgan DA, Agassandian K, et al. Ablation of the leptin receptor in the hypothalamic arcuate nucleus abrogates leptin-induced sympathetic activation. Circ Res 2011, 108: 808–12.
Rahmouni K. Leptin-induced sympathetic nerve activation: signaling mechanisms and cardiovascular consequences in obesity. Curr Hypertens Rev 2010, 6: 104–209.
Gottlieb MG, Bodanese LC, Leite LE, et al. Association between the Gln223Arg polymorphism of the leptin receptor and metabolic syndrome in free-living community elderly. Metab Syndr Relat Disord 2009, 7: 341–8.
Aizawa-Abe M, Ogawa Y, Masuzaki H, et al. Pathophysiological role of leptin in obesity-related hypertension. J Clin Invest 2000, 105: 1243–52.
Guízar-Mendoza JM, Amador-Licona N, Flores-Martínez SE, López-Cardona MG, Ahuatzin-Trémary R, Sánchez-Corona J. Association analysis of the Gln223Arg polymorphism in the human leptin receptor gene, and traits related to obesity in Mexican adolescents. J Hum Hypertens 2005, 19: 341–6.
Wauters M, Considine RV, Van Gaal LF. Human Leptin: From an Adipocyte Hormone to an Endocrine Mediator. Eur J Endocrinol 2000, 143: 293–311.
Emilsson V, Liu YL, Cawthorne MA, Morton NM, Davenport M. Expression of the functional leptin receptor mRNA in pancreatic islets and direct inhibitory action of leptin on insulin secretion. Diabetes 1997, 46: 313–6.
Salopuro T, Pulkkinen L, Lindström J, et al; Finnish Diabetes Prevention Study Group. Genetic variation in leptin receptor gene is associated with type 2 diabetes and body weight: The Finnish Diabetes Prevention Study. Int J Obes (Lond) 2005, 29: 1245–51.
Wauters M, Mertens I, Rankinen T, Chagnon M, Bouchard C, Van Gaal L. Leptin receptor gene polymorphisms are associated with insulin in obese women with impaired glucose tolerance. J Clin Endocrinol Metab 2001, 86: 3227–32.
Santaniemi M, Ukkola O, Kesäniemi YA. Tyrosine phosphatase 1B and leptin receptor genes and their interaction in type 2 diabetes. J Intern Med 2004, 256: 48–55.
Park KS, Shin HD, Park BL, et al. Polymorphisms in the leptin receptor (LEPR)—putative association with obesity and T2DM. J Hum Genet 2006, 51: 85–91.
Coenen KR, Gruen ML, Hasty AH. Obesity causes very low density lipoprotein clearance defects in low-density lipoprotein receptor-deficient mice. J Nutr Biochem 2007, 18: 727–35.
Popruk S, Tungtrongchitr R, Petmitr S, et al. Leptin, soluble leptin receptor, lipid profiles, and LEPR gene polymorphisms in Thai children and adolescents. Int J Vitam Nutr Res 2008, 78: 9–15.
Popko K, Gorska E, Wasik M, et al. Frequency of distribution of leptin receptor gene polymorphism in obstructive sleep apnea patients. J Physiol Pharmacol 2007, 58(Suppl 5): 551–61.
Takahashi-Yasuno A, Masuzaki H, Miyawaki T, et al. Leptin receptor polymorphism is associated with serum lipid levels and impairment of cholesterol lowering effect by simvastatin in Japanese men. Diabetes Res Clin Pract 2003, 62: 169–75.
Kullo IJ, Turner ST, Boerwinkle E, Kardia SL, de Andrade M. A novel quantitative trait locus on chromosome 1 with pleiotropic effects on HDL-cholesterol and LDL particle size in hypertensive sibships. Am J Hypertens 2005, 18: 1084–90.
Furusawa T, Naka I, Yamauchi T, et al. The Q223R polymorphism in LEPR is associated with obesity in Pacific Islanders. Hum Genet 2010, 127: 287–94.
Ben Ali S, Kallel A, Sediri Y, et al. LEPR p.Q223R Polymorphism influences plasma leptin levels and body mass index in Tunisian obese patients. Arch Med Res 2009, 40: 186–90.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Gu, P., Jiang, W., Chen, M. et al. Association of leptin receptor gene polymorphisms and essential hypertension in a Chinese population. J Endocrinol Invest 35, 859–865 (2012). https://doi.org/10.3275/8238
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.3275/8238